Endothelin-1 mediated signaling for increased blood-brain barrier breakdown and infarct after transient focal cerebral ischemia

Abstract

Induced endothelin-1(ET-1) expression was observed in astrocytes after experi-mental ischemic stroke, suggesting a potential role of astrocytic ET-1 in ischemicbrain injury. Previously, we showed that transgenic mice over-expressing ET-1 inastrocytes (GET mice) displayed increased cerebral infarct size and more severeneurological deficits upon focal cerebral ischemia induced by middle cerebralartery occlusion (MCAO). However, the mechanism behind astrocytic ET-1 onischemia-induced brain injury was not clear. Here, expression profile of ET systemwas examined by real-time PCR analyses. In GET brain after MCAO ET-1 levelwas further increased while ET-3 level was lowered. ETA receptor level was up-regulated while ETB receptor level remained unchanged. After MCAO GET brainshowed lower occludin level and increased Evans blue extravasation, indicatingincreased blood–brain barrier (BBB) breakdown which correlated with our resultsthat GET mice displayed increased brain swelling and brain water content. Linearregression analysis also showed correlation of severity of infarction and brainswelling with neurological deficit exacerbation. There was significant p35 down-regulation after MCAO, suggesting involvement of p25/cdk5 cell death pathwayin increased infarct formation. Caspase9 expression was also increased. Theseresults suggested that increased astrocytic ET-1 resulted in BBB disruptionpossibly leading to increased formation of brain edema and swelling, infarct andneurological deficits mediated through cdk5 pathway and, therefore, imposedadverse effects on brain injury after focal cerebral ischemia. Further globalscreening of ET-1-mediated signaling after MCAO will be discussed.Acknowledgements: Supported by RGC and UGC of Hong Kong (AoE/B-15/01).